EP0514691A2 - Nichtporöse Kollagenfolie zur therapeutischen Verwendung, und Verfahren und Vorrichtung zu ihrer Herstellung - Google Patents

Nichtporöse Kollagenfolie zur therapeutischen Verwendung, und Verfahren und Vorrichtung zu ihrer Herstellung Download PDF

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Publication number
EP0514691A2
EP0514691A2 EP92107249A EP92107249A EP0514691A2 EP 0514691 A2 EP0514691 A2 EP 0514691A2 EP 92107249 A EP92107249 A EP 92107249A EP 92107249 A EP92107249 A EP 92107249A EP 0514691 A2 EP0514691 A2 EP 0514691A2
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EP
European Patent Office
Prior art keywords
gel
collagen
drying
collagen gel
mesh
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP92107249A
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English (en)
French (fr)
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EP0514691B1 (de
EP0514691A3 (en
Inventor
Diego Furlan
Giovanni Bonfanti
Giuseppe Scappaticci
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Euroresearch SRL
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Euroresearch SRL
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Publication date
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Publication of EP0514691A2 publication Critical patent/EP0514691A2/de
Publication of EP0514691A3 publication Critical patent/EP0514691A3/en
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Publication of EP0514691B1 publication Critical patent/EP0514691B1/de
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Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/18—Manufacture of films or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A61L15/325—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/044—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D19/00—Degasification of liquids
    • B01D19/0031—Degasification of liquids by filtration
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2389/00—Characterised by the use of proteins; Derivatives thereof
    • C08J2389/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08J2389/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin

Definitions

  • Collagen is a scleroprotein widespread in nature. It represents about one third of the total proteins of the human body.
  • collagen as a stimulating agent in the cicatrization process involving an interaction effect with various growth factors, because of its capturing action on fibronectin, a glycoprotein which promotes cell attachment and the migration and replication of the resultant cells (see "Il collageno nella cicatrizzazione" by B. Palmieri, publ. Artestampa, January 1990, pp. 40-42) and other actions which are still not totally clear.
  • the known collagen product using a particular non-denaturing process, is prepared in stable form by a process of extraction from animal organs rich in this scleroprotein, purification and subsequent lyophilization.
  • the final product is in the form of mats of greater or lesser thickness, characterised by high absorbent power (exudates and liquids in general) because of its structure in the form of fibres which are spaced apart and branched in such a manner as to make a large specific surface available for absorption (up to 50 times its weight).
  • high absorbent power exudates and liquids in general
  • the hydrophilic nature of collagen also greatly favours this absorbent power.
  • the role of collagen in cicatrization is characterised by collagen/platelet interaction and the formation of a bond between the collagen, the fibronectin and the growth factors, molecules which are known to be implicated in regulating the cicatrization process (see pages 45-46 of the aforesaid text).
  • the present invention provides a product which while maintaining the rapid cicatrization characteristics of collagen, at the same time prevents excessive evaporation, allows constant inspection of the bed of the wound without having to be removed (transparency), is simple and practical to use, adheres satisfactorily to the injured surface, does not require frequent replacement, can transpire to allow oxygenation of the bed of the wound while preventing its contamination by bacteria, is absorbable but not soluble in the biological liquids with which it comes into contact, unless by specific enzymatic action, and is structurally homogeneous.
  • Another important characteristic of the collagen according to the invention is that of being suitable as interposition material for preventing accretions in the internal surgery operations.
  • Type I collagen was used as defined in Table 1 on page 3 of the aforestated text, this having the characteristic of being insoluble in the various types of biological liquids.
  • Type I collagen present in the skin represents about 80% of the total located in the deep dermis, 90-95% in the tendons and 100% in the bones. Type I collagen is therefore the most biologically similar to that present in the human skin.
  • the filtering which is done under vacuum, uses a special filter, indicative (but not limitative) characteristics of which are given hereinafter, and allows practically total elimination of the inevitable air bubbles which form during gelling and are difficult to eliminate given the viscosity of collagen gel.
  • the filtered gel is collected in a closed vessel maintained under vacuum and constructed in such a manner that the filtered gel runs along vessel partition walls located below the filter mesh and structured to produce a continuous liquid film which does not allow further air absorption after filtration, following inclusion of air bubbles.
  • the filtered gel is further maintained under vacuum at 20-25 mmHg for a further hour to allow total elimination of any air bubbles which may still be present in the gel.
  • the filter required for filtering the collagen gel which besides eliminating the solid particles, which are retained on the mesh, also eliminates the air bubbles contained in it, consists of an upper cylindrical stainless steel shell provided with a scraping stirrer to keep the collagen gel mixed and to remove solid particles from the mesh so that they do not clog it.
  • the bottom of the cylindrical shell houses a stainless steel mesh with a mesh size of less than 0.1 mm (Taurail meshes have been found to be particularly effective).
  • the lower part (below the mesh) consists of a cylindrical shell in which vacuum can be generated by a suitable pump.
  • the air bubbles contained in the gel which filters through the mesh increase considerably in volume because of the vacuum.
  • the filter mesh At about 3 mm below the filter mesh there is a device consisting of a series of stainless steel plates which are vertically or raking placed and parallel between them. The filtered gel descends along these plates in the form of a continuous liquid film and runs by gravity towards the bottom of the vessel.
  • the filtered gel obtained as described free from extraneous particles and air bubbles and perfectly clear and transparent, can then be used for preparing films of desired thickness and diameter.
  • the described trays loaded with the gel in a controlled environment (relative humidity 60-80% temperature 20-22°C, environment class 10,000 or less) are placed in a suitable controlled drying oven where they are left to stand for at least two hours to obtain perfect gel thickness uniformity.
  • the oven is purged with a nitrogen stream for about 30 minutes to totally eliminate air and remove oxygen, in order to ensure constant operating conditions and prevent possible oxidation.
  • Drying is effected in a nitrogen stream under closed cycle.
  • the reference numeral 1 indicates the drying trays resting on perforated side walls
  • V indicates the fan for circulating nitrogen through the apparatus
  • N2 indicates the nitrogen feed valve
  • GF indicates the refrigeration unit with coil
  • S represents a parallel plate device for separating condensate droplets
  • T1 indicates a first thermometer
  • SC indicates the condensed water discharge
  • R indicates the heating device
  • T2 indicates a second thermometer
  • I1 indicates a first hygrometer
  • MO indicates an oxygen meter (analyzer)
  • Sg indicates the gas discharge
  • Tr indicates an overpressure trap
  • I2 indicates a second hygrometer.
  • the oven is arranged in this manner to satisfy the following requirements:
  • the H2O content of the product must not be higher than 20% by weight. It is preferable to achieve a higher level of drying (down to 2% or 3% of H2O), in particular to ensure proper elimination of the acetic acid present in the initial gel.
  • the dried product obtained easily reabsorbs moisture from the environment, while being maintained within the maximum limit of 20%.
  • Nitrogen temperature after cooling -15°C T1
  • Nitrogen temperature after heating 26-28°C T2. Time about 12 hours. Relative humidity entry to drying region (point I1) 6-7%. Relative humidity exit of drying region (point I2) 45-50%.
  • the nitrogen flow rate through the drier is adjusted on the basis of the required degree of drying.
  • a semi-transparent film with a thickness of about 200 micron is obtained.
  • the thickness can vary in general between 0.02 and 2 mm.
  • the product obtained in this manner is sterilized by irradiation with gamma rays and used in the treatment of burns and generally all cases of skin removal or damage.
  • the result is excellent both in terms of tolerance (no case of allergenicity or hypersensitivity to the medicament has been recorded, the native characteristic of the product remaining unaltered during the process) and in terms of pain attenuation.
  • the cicatrization time is very rapid and product absorption considerably longer compared with equivalent treatment using lyophilized collagen (sponge) and consequently there is lesser need to replace it. Exudate loss is very low, and much lower than that when using lyophilized collagen.
  • the transparency of the product means that the progress of the injury can be viewed without the need to remove the collagen sheet (generally a painful procedure).
  • the product can be presented in the form of sheets of different dimensions (square, rectangular, round, elliptical or others) supported or not supported by adhesives (such as plasters) or by sheets of inert substances such as nylon, polyurethane, polyethylene etc., or associated during the drying process, or subsequently, with pharmacologically active substances.
EP92107249A 1991-05-23 1992-04-29 Nichtporöse Kollagenfolie zur therapeutischen Verwendung, und Verfahren und Vorrichtung zu ihrer Herstellung Expired - Lifetime EP0514691B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI911423 1991-05-23
ITMI911423A IT1249315B (it) 1991-05-23 1991-05-23 Lamina di collageno non poroso per uso terapeutico, metodo ed apparecchiature per ottenerlo

Publications (3)

Publication Number Publication Date
EP0514691A2 true EP0514691A2 (de) 1992-11-25
EP0514691A3 EP0514691A3 (en) 1993-03-31
EP0514691B1 EP0514691B1 (de) 1996-01-03

Family

ID=11359972

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92107249A Expired - Lifetime EP0514691B1 (de) 1991-05-23 1992-04-29 Nichtporöse Kollagenfolie zur therapeutischen Verwendung, und Verfahren und Vorrichtung zu ihrer Herstellung

Country Status (8)

Country Link
EP (1) EP0514691B1 (de)
JP (1) JP3423330B2 (de)
KR (1) KR100229304B1 (de)
CN (1) CN1066790A (de)
AT (1) ATE132517T1 (de)
CA (1) CA2064993C (de)
DE (1) DE69207263T2 (de)
IT (1) IT1249315B (de)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6309454B1 (en) 2000-05-12 2001-10-30 Johnson & Johnson Medical Limited Freeze-dried composite materials and processes for the production thereof
WO2003030882A1 (en) * 2001-10-12 2003-04-17 Kosmos Pharma Thin film with non-self-aggregating uniform heterogeneity, process for their production and drug delivery systems made thereform
JP2006516634A (ja) * 2003-01-30 2006-07-06 モノソル・アールエックス・エルエルシー 非自己凝集性で均一な混成を示す薄いフィルム、およびそれから作製した薬物送達システム
JP2007500252A (ja) * 2003-05-28 2007-01-11 モノソル・アールエックス・エルエルシー ポリエチレンオキシドフィルムおよびそれからなる薬物送達系
US7666337B2 (en) 2002-04-11 2010-02-23 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
US7972618B2 (en) 2006-09-20 2011-07-05 Monosol Rx, Llc Edible water-soluble film containing a foam reducing flavoring agent
US8652378B1 (en) 2001-10-12 2014-02-18 Monosol Rx Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
US8765167B2 (en) 2001-10-12 2014-07-01 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US8900497B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for making a film having a substantially uniform distribution of components
US8900498B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for manufacturing a resulting multi-layer pharmaceutical film
US8906277B2 (en) 2001-10-12 2014-12-09 Monosol Rx, Llc Process for manufacturing a resulting pharmaceutical film
US9108340B2 (en) 2001-10-12 2015-08-18 Monosol Rx, Llc Process for manufacturing a resulting multi-layer pharmaceutical film
US9592125B2 (en) 2006-12-22 2017-03-14 Laboratoire Medidom S.A. In situ system for intra-articular chondral and osseous tissue repair
US10272607B2 (en) 2010-10-22 2019-04-30 Aquestive Therapeutics, Inc. Manufacturing of small film strips
US10285910B2 (en) 2001-10-12 2019-05-14 Aquestive Therapeutics, Inc. Sublingual and buccal film compositions
US10821074B2 (en) 2009-08-07 2020-11-03 Aquestive Therapeutics, Inc. Sublingual and buccal film compositions
US11077068B2 (en) 2001-10-12 2021-08-03 Aquestive Therapeutics, Inc. Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US11191737B2 (en) 2016-05-05 2021-12-07 Aquestive Therapeutics, Inc. Enhanced delivery epinephrine compositions
US11207805B2 (en) 2001-10-12 2021-12-28 Aquestive Therapeutics, Inc. Process for manufacturing a resulting pharmaceutical film
US11273131B2 (en) 2016-05-05 2022-03-15 Aquestive Therapeutics, Inc. Pharmaceutical compositions with enhanced permeation

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US8663687B2 (en) 2001-10-12 2014-03-04 Monosol Rx, Llc Film compositions for delivery of actives
US7425292B2 (en) 2001-10-12 2008-09-16 Monosol Rx, Llc Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom
US7910641B2 (en) 2001-10-12 2011-03-22 Monosol Rx, Llc PH modulated films for delivery of actives
US8017150B2 (en) 2002-04-11 2011-09-13 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
JP4621563B2 (ja) * 2005-08-26 2011-01-26 新田ゼラチン株式会社 皮膚用保水シート
US8475832B2 (en) 2009-08-07 2013-07-02 Rb Pharmaceuticals Limited Sublingual and buccal film compositions
WO2011156711A1 (en) 2010-06-10 2011-12-15 Schobel Alexander M Nanoparticle film delivery systems
CN109364570B (zh) 2018-12-19 2021-02-02 武汉华星光电半导体显示技术有限公司 一种过滤装置及过滤方法
JP7311983B2 (ja) * 2019-03-01 2023-07-20 大日本印刷株式会社 ゲル膜の製造方法およびゲル膜

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0376931A1 (de) 1984-12-24 1990-07-04 Collagen Corporation Verfahren zur Herstellung von Membranen aus Kollagen für medizinische Anwendungen

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1596789A (de) * 1968-11-27 1970-06-22
IT946066B (it) * 1971-11-17 1973-05-21 Sir Soc Italiana Resine Spa Catalizzatori per la produzione dell ossido di etilene per ossi dazione dell etilene
US4948540A (en) * 1988-08-01 1990-08-14 Semex Medical, Inc. Method of preparing collagen dressing sheet material

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0376931A1 (de) 1984-12-24 1990-07-04 Collagen Corporation Verfahren zur Herstellung von Membranen aus Kollagen für medizinische Anwendungen

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6309454B1 (en) 2000-05-12 2001-10-30 Johnson & Johnson Medical Limited Freeze-dried composite materials and processes for the production thereof
JP2015129183A (ja) * 2001-10-12 2015-07-16 モノソル・アールエックス・エルエルシー 自己凝集しない均一な異種性を有する薄膜、その生成方法、およびそれから製造した薬物送達系
US11207805B2 (en) 2001-10-12 2021-12-28 Aquestive Therapeutics, Inc. Process for manufacturing a resulting pharmaceutical film
US8900497B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for making a film having a substantially uniform distribution of components
US8765167B2 (en) 2001-10-12 2014-07-01 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US11077068B2 (en) 2001-10-12 2021-08-03 Aquestive Therapeutics, Inc. Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US9931305B2 (en) 2001-10-12 2018-04-03 Monosol Rx, Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
WO2003030882A1 (en) * 2001-10-12 2003-04-17 Kosmos Pharma Thin film with non-self-aggregating uniform heterogeneity, process for their production and drug delivery systems made thereform
EP2351557A1 (de) * 2001-10-12 2011-08-03 MonoSol RX LLC Dünner film ohne selbtaggregation mit gleichmässiger heterogenität, verfahren zu deren herstellung, sowie daraus hergestellte arzneistoffabgabesysteme
US8900498B2 (en) 2001-10-12 2014-12-02 Monosol Rx, Llc Process for manufacturing a resulting multi-layer pharmaceutical film
US8652378B1 (en) 2001-10-12 2014-02-18 Monosol Rx Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
US10285910B2 (en) 2001-10-12 2019-05-14 Aquestive Therapeutics, Inc. Sublingual and buccal film compositions
US9855221B2 (en) 2001-10-12 2018-01-02 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
JP2005511522A (ja) * 2001-10-12 2005-04-28 モノソル・アールエックス・エルエルシー 自己凝集しない均一な異種性を有する薄膜、その生成方法、およびそれから製造した薬物送達系
US8906277B2 (en) 2001-10-12 2014-12-09 Monosol Rx, Llc Process for manufacturing a resulting pharmaceutical film
US10888499B2 (en) 2001-10-12 2021-01-12 Aquestive Therapeutics, Inc. Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom
US9108340B2 (en) 2001-10-12 2015-08-18 Monosol Rx, Llc Process for manufacturing a resulting multi-layer pharmaceutical film
US10111810B2 (en) 2002-04-11 2018-10-30 Aquestive Therapeutics, Inc. Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom
US7666337B2 (en) 2002-04-11 2010-02-23 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
JP2006516634A (ja) * 2003-01-30 2006-07-06 モノソル・アールエックス・エルエルシー 非自己凝集性で均一な混成を示す薄いフィルム、およびそれから作製した薬物送達システム
JP2011068689A (ja) * 2003-01-30 2011-04-07 Monosol Rx Llc 非自己凝集性で均一な混成を示す薄いフィルム、およびそれから作製した薬物送達システム
JP4795962B2 (ja) * 2003-05-28 2011-10-19 モノソル・アールエックス・エルエルシー ポリエチレンオキシドフィルムおよびそれからなる薬物送達系
JP2007500252A (ja) * 2003-05-28 2007-01-11 モノソル・アールエックス・エルエルシー ポリエチレンオキシドフィルムおよびそれからなる薬物送達系
US7972618B2 (en) 2006-09-20 2011-07-05 Monosol Rx, Llc Edible water-soluble film containing a foam reducing flavoring agent
US9592125B2 (en) 2006-12-22 2017-03-14 Laboratoire Medidom S.A. In situ system for intra-articular chondral and osseous tissue repair
US10821074B2 (en) 2009-08-07 2020-11-03 Aquestive Therapeutics, Inc. Sublingual and buccal film compositions
US10940626B2 (en) 2010-10-22 2021-03-09 Aquestive Therapeutics, Inc. Manufacturing of small film strips
US10272607B2 (en) 2010-10-22 2019-04-30 Aquestive Therapeutics, Inc. Manufacturing of small film strips
US11191737B2 (en) 2016-05-05 2021-12-07 Aquestive Therapeutics, Inc. Enhanced delivery epinephrine compositions
US11273131B2 (en) 2016-05-05 2022-03-15 Aquestive Therapeutics, Inc. Pharmaceutical compositions with enhanced permeation

Also Published As

Publication number Publication date
KR100229304B1 (ko) 1999-11-01
JP3423330B2 (ja) 2003-07-07
CA2064993A1 (en) 1992-11-24
ITMI911423A0 (it) 1991-05-23
IT1249315B (it) 1995-02-22
EP0514691B1 (de) 1996-01-03
ATE132517T1 (de) 1996-01-15
JPH05117162A (ja) 1993-05-14
ITMI911423A1 (it) 1992-11-23
DE69207263D1 (de) 1996-02-15
DE69207263T2 (de) 1996-05-15
EP0514691A3 (en) 1993-03-31
KR920021161A (ko) 1992-12-18
CN1066790A (zh) 1992-12-09
CA2064993C (en) 2005-01-18

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